Researchers describe strategy to develop first broad-spectrum antiviral drug
By studying the rare person — about one in a million — who can fight off viral infections more effectively than everyone else, investigators at the Icahn School of Medicine at Mount Sinai have developed a strategy to help the rest of us achieve this enhanced anti-viral state.
Their research, published in Nature Communications, provides a path toward creation of the first broad-spectrum antiviral drug. None currently exists.
The international research team demonstrated in human cell and animal studies that switching off a single gene bolsters immunity against seven viruses, including the extremely dangerous Nipah and Rift Valley fever viruses.
"We also have evidence suggesting the strategy protects against Zika infection, and we plan to test Ebola as soon as possible," said the study's lead investigator, Dusan Bogunovic, PhD, Assistant Professor of Microbiology and Pediatrics at the Icahn School of Medicine at Mount Sinai.
"The idea is to develop a pill that people can use to protect against pandemics — or even to help an individual stop an emerging cold sore," he said.
The scientists studied ISG15, a gene whose activity is linked to type 1 interferon, which regulates the immune system's response to viral infection.
Twenty years ago, scientists demonstrated that mice that do not have the ISG15 gene are more susceptible to viral infections. But in humans, the opposite is true; those rare humans who do not have the gene have an extremely robust response against viral infection, as shown by the Mount Sinai team, which includes collaborating international researchers at the Pasteur Institute in France.
"To our pleasant surprise, what doesn't work in mice works beautifully in humans. If you, as a human, don't have that gene, you may be more able to fight off viral infections than others," said Dr. Bogunovic.
"Additionally, if you do get infected, you control it better. You are basically like a vaccine in yourself," he said. "You don't necessarily experience the same range and degree of symptoms, but you still develop antibodies and T-cells and everything you need to be ready for the next infection."
The researchers found that the normal role of ISG15 in humans is to help turn off the type 1 interferon response to a viral invader once it has been activated and is working. "It fine-tunes the very end of shutting off that inflammation. So when you don't have the gene, your body continues to trickle out type 1 interferon, thus continually priming the body against viral invaders," Dr. Bogunovic said. "So you are persistently ready to take on viruses."
Such long-term antiviral resiliency comes at a price for those lacking the ISG15 gene, he added — many of those individuals developed occasional seizures and detectable auto-antibodies, although none have yet developed autoimmune disorders.
"We believe a drug that turns off ISG15 in humans for a brief amount of time would help many people facing an emerging viral infection — but of course, all this needs to be tested," Dr. Bogunovic said. He added that his team is now screening millions of small molecules to find a pill that can provide such an antiviral boost.
Study co-authors include, from the Department of Microbiology at the Icahn School of Medicine at Mount Sinai: Scott D. Speer, PhD, Sofija Buta, MS, Li Qian, MD, PhD, Frederic Vigant, PhD, Thomas J. Gardner, PhD, Mark Hermann, MR, James Duehr, MR, Domenico Tortorella, PhD, Benhur Lee, MD, and Adolfo García-Sastre, PhD; Zhi Li, MD, Béatrice Payelle-Brogard, PhD, Erminia Rubino, MS, Véronique Francois-Newton, PhD, Coralie F. Daussy, PhD, and Sandra Pellegrini, PhD from the Institut Pasteur in Paris; Tim Wedeking, PhD and Jacob Piehler, PhD, from University of Osnabrück, Osnabrück, Germany; Ozden Sanal, MD and Ilhan Tezcan, MD from Hacettepe University, Ankara, Turkey; Nahal Mansouri, MD, Payam Tabarsi, MD, and Davood Mansouri, MD from Shahid Beheshti University of Medical Sciences, Teheran, Iran; Marisela R. Rodriguez, PhD and Deborah J. Lenschow, PhD from Washington University School of Medicine; and Alexander N. Freiberg, PhD from the University of Texas Medical Branch. The study was financially supported by NIH R01 grants AI101820, A1080672; National Institute of Allergy and Infectious Diseases grant R00AI106942-02; an American Heart Association pre-doctoral fellowship and a USPHS Institutional Research Training Awards T32-AI07647; and NRSA T32 AR07279-30.
About the Mount Sinai Health System
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services–from community-based facilities to tertiary and quaternary care.
The System includes approximately 6,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is ranked as one of the nation's top 10 hospitals in Geriatrics, Cardiology/Heart Surgery, and Gastroenterology, and is in the top 25 in five other specialties in the 2015-2016 "Best Hospitals" issue of U.S. News & World Report. Mount Sinai's Kravis Children's Hospital also is ranked in seven out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology, while Mount Sinai Beth Israel is ranked regionally.
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